A Phase 1, Double-blinded, Placebo-Controlled Clinical Trial to Evaluate the Safety and Immunogenicity of HEV-239 (Hecolin®) Vaccine in Healthy US Adults.

INTRODUCTION: Establishing the safety and immunogenicity of a hepatitis E virus vaccine in multiple populations could facilitate broader access and prevent maternal and infant mortality. METHODS: We conducted a phase 1, randomized, double-blinded, placebo-controlled (4:1 vaccine: placebo) trial of 30 µg HEV-239 (Hecolin®, Xiamen Innovax Biotech Company Limited, China) administered intramuscularly in healthy US adults aged 18-45 years. Participants were vaccinated on days 1, 29, and 180. Participants reported solicited local and systemic reactions for 7 days following vaccination and were followed through 12 months after enrollment for safety and immunogenicity (IgG, IgM). RESULTS: Solicited local and systemic reactions between treatment and placebo group were similar and overall mild. No participants experienced serious adverse events related to HEV-239. All participants receiving HEV-239 seroconverted at one month following the first dose and remained seropositive throughout the study. HEV-239 elicited a robust hepatitis E IgG response that peaked one month following the second dose (Geometric Mean Concentration (GMC) 6.16; 95% CI 4.40-8.63), was boosted with the third dose (GMC 11.50; 95% CI 7.90-16.75) and persisted through 6 months. CONCLUSIONS: HEV-239 is safe and elicits a durable immune response through at least 6 months after the third dose in healthy US adults. CLINICAL TRIALS REGISTRATION: NCT03827395. Safety Study of Hepatitis E Vaccine (HEV239) - Full Text View - ClinicalTrials.gov.

Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study.

BACKGROUND: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial. PATIENTS AND METHODS: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion. RESULTS: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy. CONCLUSIONS: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.

Parieto-Occipital Injury on Diffusion MRI Correlates with Poor Neurologic Outcome following Cardiac Arrest.

BACKGROUND AND PURPOSE: MR imaging of the brain provides unbiased neuroanatomic evaluation of brain injury and is useful for neurologic prognostication following cardiac arrest. Regional analysis of diffusion imaging may provide additional prognostic value and help reveal the neuroanatomic underpinnings of coma recovery. The purpose of this study was to evaluate global, regional, and voxelwise differences in diffusion-weighted MR imaging signal in patients in a coma after cardiac arrest. MATERIALS AND METHODS: We retrospectively analyzed diffusion MR imaging data from 81 subjects who were comatose for >48 hours following cardiac arrest. Poor outcome was defined as the inability to follow simple commands at any point during hospitalization. ADC differences between groups were evaluated across the whole brain, locally by using voxelwise analysis and regionally by using ROI-based principal component analysis. RESULTS: Subjects with poor outcome had more severe brain injury as measured by lower average whole-brain ADC (740 [SD, 102] × 10-6 mm2/s versus 833 [SD, 23] × 10-6 mm2/s, P < .001) and larger average volumes of tissue with ADC below 650 × 10-6 mms/s (464 [SD, 469] mL versus 62 [SD, 51] mL, P < .001). Voxelwise analysis showed lower ADC in the bilateral parieto-occipital areas and perirolandic cortices for the poor outcome group. ROI-based principal component analysis showed an association between lower ADC in parieto-occipital regions and poor outcome. CONCLUSIONS: Brain injury affecting the parieto-occipital region measured with quantitative ADC analysis was associated with poor outcomes after cardiac arrest. These results suggest that injury to specific brain regions may influence coma recovery.

Risk of thromboembolism in non-small-cell lung cancers patients with different oncogenic drivers, including ROS1, ALK, and EGFR mutations.

BACKGROUND: Anaplastic lymphoma kinase-positive (ALK+) and ROS proto-oncogene 1 (ROS1)-positive (ROS1+) lung cancers have been reported to be associated with an elevated risk of thromboembolic events. This study aimed to assess the long-term risk of developing thromboembolism (TE) in ROS1+ lung cancer and to compare it with other oncogenic drivers in the Asian population. MATERIALS AND METHODS: We retrospectively enrolled a cohort of ROS1+ lung adenocarcinoma in a medical center in Taiwan and a comparison cohort of ALK+ and epidermal growth factor receptor-positive (EGFR+) lung cancers. Venous and arterial TEs were identified throughout the cancer course, and the incidence rate was calculated. RESULTS: We enrolled 44 ROS1+, 98 ALK+, and 168 EGFR+ non-small-cell lung cancer (NSCLC) patients. A total of 11 (25%), 36 (36.7%), and 38 (22.6%) patients in the ROS1, ALK, and EGFR cohorts, respectively, were diagnosed with thromboembolic events throughout the follow-up course of the disease (P = 0.042). The incidence rates were 99.0, 91.9, and 82.5 events per 1000 person-years for the ROS1, ALK, and EGFR cohorts, respectively. The majority of thrombosis events in the ROS1 (91.6%) and ALK (85.4%) cohorts were venous. On the contrary, 43.2% of thromboembolic events were arterial in the EGFR cohort. A higher proportion of thromboembolic events were noted during cancer diagnosis in the ROS1 cohort (36.3%) than in the ALK (16.7%) and EGFR (10.5%) cohorts. The stage was the only clinical variable associated with thromboembolic risk. There was a significant difference in survival between patients with and without TE in the EGFR cohort, but not in the ALK and ROS1 cohorts. CONCLUSIONS: Although ROS1+ and ALK+ NSCLCs had a higher cumulative incidence of TE than EGFR+ NSCLC, the person-year incidence rates were similar among the three groups. EGFR-mutated NSCLC had more arterial events. Nevertheless, ALK+ lung cancer had higher venous events than EGFR-mutated lung cancer.

Contributions of Stereotactic EEG Electrodes in Grey and White Matter to Speech Activity Detection.

Recent studies have shown it is possible to decode and synthesize speech directly using brain activity recorded from implanted electrodes. While this activity has been extensively examined using electrocorticographic (ECoG) recordings from cortical surface grey matter, stereotactic electroen-cephalography (sEEG) provides comparatively broader coverage and access to deeper brain structures including both grey and white matter. The present study examines the relative and joint contributions of grey and white matter electrodes for speech activity detection in a brain-computer interface.

Recurrence of pericardial effusion after different procedure modalities in patients with non-small-cell lung cancer.

BACKGROUND: Lung cancer with related pericardial effusion is not rare. Intervention is a crucial step for symptomatic effusion. It is unknown, however, whether the different invasive interventions for pericardial effusion result in different survival outcomes. This study analyzed the clinical characteristics and prognostic factors for patients with non-small-cell lung cancer (NSCLC) who have undergone different procedures. METHODS: From January 2006 to June 2018, we collected data from patients with NSCLC who have received invasive intervention for pericardial effusions. The patients were divided into three categories: simple pericardiocentesis, balloon pericardiotomy, and surgical pericardiectomy. Kaplan-Meier curve and log-rank test were used to analyze the pericardial effusion recurrence-free survival (RFS) and overall survival (OS). RESULTS: A total of 244 patients were enrolled. Adenocarcinoma (83.6%) was the major NSCLC subtype. Invasive intervention, including simple pericardiocentesis, balloon pericardiotomy, and surgical pericardiectomy, had been carried out on 52, 170, and 22 patients, respectively. The 1-year RFS rates in simple pericardiocentesis, balloon pericardiotomy, and surgical pericardiectomy were 19.2%, 31.2%, and 31.8%, respectively (P = 0.128), and the median RFS was 1.67, 5.03, and 8.32 months, respectively (P = 0.008). There was no significant difference in OS, however, with the median OS at 1.67, 6.43, and 8.32 months, respectively (P = 0.064). According to the multivariable analysis, the gravity in pericardial fluid analysis, receiving systemic therapy after pericardial effusion, and the time period from stage IV lung cancer to the presence of pericardial effusion were independent prognostic factors for pericardial effusion RFS and OS. CONCLUSIONS: Patients who have undergone simple pericardiocentesis alone for the management of NSCLC-related pericardial effusion have lower 1-year RFS rates than those who have undergone balloon pericardiotomy and surgical pericardiectomy. Therefore, balloon pericardiotomy and surgical pericardiectomy should be carried out for patients with NSCLC-related pericardial effusion if tolerable.

Prefrontal High Gamma in ECoG Tags Periodicity of Musical Rhythms in Perception and Imagination.

Rhythmic auditory stimuli are known to elicit matching activity patterns in neural populations. Furthermore, recent research has established the particular importance of high-gamma brain activity in auditory processing by showing its involvement in auditory phrase segmentation and envelope tracking. Here, we use electrocorticographic (ECoG) recordings from eight human listeners to see whether periodicities in high-gamma activity track the periodicities in the envelope of musical rhythms during rhythm perception and imagination. Rhythm imagination was elicited by instructing participants to imagine the rhythm to continue during pauses of several repetitions. To identify electrodes whose periodicities in high-gamma activity track the periodicities in the musical rhythms, we compute the correlation between the autocorrelations (ACCs) of both the musical rhythms and the neural signals. A condition in which participants listened to white noise was used to establish a baseline. High-gamma autocorrelations in auditory areas in the superior temporal gyrus and in frontal areas on both hemispheres significantly matched the autocorrelations of the musical rhythms. Overall, numerous significant electrodes are observed on the right hemisphere. Of particular interest is a large cluster of electrodes in the right prefrontal cortex that is active during both rhythm perception and imagination. This indicates conscious processing of the rhythms' structure as opposed to mere auditory phenomena. The autocorrelation approach clearly highlights that high-gamma activity measured from cortical electrodes tracks both attended and imagined rhythms.

COVID-19: Initial experience of an international group of hand surgeons.

The emergence of the COVID-19 pandemic has severely affected medical treatment protocols throughout the world. While the pandemic does not affect hand surgeons at first glance, they have a role to play. The purpose of this study was to describe the different measures that have been put in place in response to the COVID-19 pandemic by hand surgeons throughout the world. The survey comprised 47 surgeons working in 34 countries who responded to an online questionnaire. We found that the protocols varied in terms of visitors, health professionals in the operating room, patient waiting areas, wards and emergency rooms. Based on these preliminary findings, an international consensus on hand surgery practices for the current viral pandemic, and future ones, needs to be built rapidly.

The addition of Valproic acid to concurrent radiation therapy and temozolomide improves patient outcome: a Correlative analysis of RTOG 0525, SEER and a Phase II NCI trial.

PURPOSE/OBJECTIVES: Valproic Acid (VPA) is an antiepileptic agent with HDACi (histone deacetylase inhibitor) activity shown to radiosensitize glioblastoma (GBM) cells. We evaluated the addition of VPA to standard radiation therapy (RT) and temozolomide (TMZ) in an open-label, phase II study (NCI-06-C-0112). The intent of the current study was to compare our patient outcomes with modern era standard of care data (RTOG 0525) and general population data (SEER 2006-2013). MATERIALS/METHODS: 37 patients with newly diagnosed GBM were treated in a phase II NCI trial with daily VPA (25 mg/kg) in addition to concurrent RT and TMZ (2006 - 2013) and 411 patients with newly diagnosed GBM were treated in the standard TMZ dose arm of RTOG 0525 (2006 - 2008). Using the SEER database, adult patients (age > 15) with diagnostic codes 9440-9443 (third edition (IDC-O-3) diagnosed between 2006 - 2013 were identified and 6083 were included in the analysis. Kaplan-Meier method was used to estimate OS and PFS. The effect of patient characteristics and clinical factors on OS and PFS was analyzed using univariate analysis and a Cox regression model. A landmark analysis was performed to correlate recurrence to OS and conditional probabilities of surviving an additional 12 months at diagnosis, 6, 12, 18, 24 and 30 months were calculated for both the trial data and the SEER data. RESULTS: Updated median OS in the NCI cohort was 30.9m (22.2- 65.6m), compared to RTOG 0525 18.9m (16.8-20.3m) (p= 0.007) and the SEER cohort of 11m. Median PFS in the NCI cohort was 11.1m (6.6 - 49.6m) compared to RTOG 0525 with a median PFS of 7.5m (6.9-8.2m) (p = 0.004). Younger age, class V RPA and MGMT status were significant for PFS in both the NCI cohort and the RTOG 0525 cohort, in addition KPS was also significant for OS. In comparison to RTOG 0525, the population in the NCI cohort had a more favorable KPS and RPA, and a higher proportion of patients receiving bevacizumab after protocol therapy however with the exception of RPA (V) (8% vs 18%) (0.026), the effects of these factors on PFS and OS were not significantly different between the two cohorts. CONCLUSION: Previously reported improvements in PFS and OS with the addition of VPA to concurrent RT and TMZ in the NCI phase II study were confirmed by comparison to both a trial population receiving standard of care (RTOG 0525) and a contemporary SEER cohort. These results provide further justification of a phase III trial of VPA/RT/TMZ.

'Nausicaa' compression suture: a simple and effective alternative to hysterectomy in placenta accreta spectrum and other causes of severe postpartum haemorrhage.

Postpartum haemorrhage (PPH), especially resulting from placenta accreta spectrum (PAS), has become a worldwide concern in maternity care. We describe a novel method of uterine compression sutures (the 'Nausicaa' technique) as an alternative to hysterectomy for patients who have suffered from major PPH. We applied this technique in 68 patients with major PPH during caesarean section (including 43 patients with PAS, 20 patients with placenta praevia totalis, and five patients with uterine atony), and none of these patients required further hysterectomy. We conclude that our Nausicaa suture is a simple and feasible alternative to hysterectomy in patients suffering from major PPH.

An in vitro bacterial surface migration assay underneath sterile barrier material commonly found in a hospital setting.

OBJECTIVE: To determine what barrier material used in hospital neonatal intensive care units most effectively blocks bacterial migration. STUDY DESIGN: Bacterial migration distance was compared across simple and complex solid media using Escherichia coli, an early and common neonatal gut colonizer, and Staphylococcus aureus, a common skin bacterium, across polystyrene, medical-grade silicone, hydrocolloid dressing and transparent film dressing as barrier materials on complex solid media. RESULTS: Bacterial migration was significantly greater on complex versus simple solid media. Bacteria migrated farthest beneath hydrocolloid dressing and transparent film dressing, while migration underneath polystyrene and medical-grade silicone was generally comparable to no barrier. CONCLUSIONS: Commonly used hydrocolloid dressing and transparent film dressing surprisingly increases bacterial migration, possibly by providing a wet capillary surface for bacteria to attach to or inducing biofilm formation. Using polystyrene or silicone to interface with the site of catheter insertion may best avoid a bacterial wicking phenomenon.

Concurrent carpal tunnel syndrome and pronator syndrome: A retrospective study of 21 cases.

PURPOSE: Concurrent carpal tunnel syndrome and pronator syndrome are rarely considered and the proximal compression sites are easily overlooked. We retrospectively studied 21 concurrent cases in our series from 2009 to 2015 and report the results. PATIENTS AND METHODS: The typical symptoms were pain, tingling, and numbness of the radial 3½ digits. If paresthesia involved the thenar eminence and proximal forearm pain was noted in cases of carpal tunnel syndrome, carpal tunnel syndrome combined with pronator syndrome was considered. Additionally, nocturnal paresthesia symptoms are absent in pronator syndrome. Therefore, if nocturnal symptoms occurred in pronator syndrome, carpal tunnel syndrome was considered. We included concurrent carpal tunnel syndrome and pronator syndrome. We used arthroscopic release of the transverse carpal ligament and open decompression for the pronator teres in cases that underwent surgery for the first time. However, recurrent carpal tunnel cases were treated with the open carpal tunnel release and open pronator decompression procedure in our hospital. The two-point discrimination was used for evaluation of sensory deficit. The grip and pinch (thumb tip to index) strength were measured by dynamometry and pinch gauge respectively. RESULTS: We retrospectively reviewed 344 cases of sustained carpal tunnel syndrome or pronator syndrome from the medical records of our institution. Of the 344 cases, 322 involved carpal tunnel syndrome alone, 1 involved pronator syndrome alone, and 21 involved carpal tunnel syndrome combined with pronator syndrome. The 21 cases of carpal tunnel syndrome combined with pronator syndrome were included in our study. Among the total cases of carpal tunnel syndrome, 6% (21/343) had pronator syndrome. The patients included 3 men and 18 women with a mean age of 52 years (range: 42-69 years). Electromyography (EMG) and nerve conduction studies were routinely performed. Postoperative evaluation showed that 15 out of 21 patients (71%) were completely relieved of pain and paresthesia and had no sensory deficit, satisfied strength improved (>85% of the opposite hand). Six patients (29%) had occasional paresthesia and pain, but no sensory deficit; grip and pinch strength deficit were recorded (<50% of the opposite hand). Six cases of these partially relieved patients had recurrent carpal tunnel syndrome but no one needed to perform tendon transfer for thenar muscle atrophy. CONCLUSION: It is important to consider the diagnosis of double crush syndrome of the median nerve, as carpal tunnel syndrome combined with pronator syndrome may impede treatment of the carpal tunnel syndrome.

Utility of 18F-fluoroestradiol (18F-FES) PET/CT imaging as a pharmacodynamic marker in patients with refractory estrogen receptor-positive solid tumors receiving Z-endoxifen therapy.

BACKGROUND: Z-endoxifen is the most potent of the metabolites of tamoxifen, and has the potential to be more effective than tamoxifen because it bypasses potential drug resistance mechanisms attributable to patient variability in the expression of the hepatic microsomal enzyme CYP2D6. 18F-FES is a positron emission tomography (PET) imaging agent which selectively binds to estrogen receptor alpha (ER-α) and has been used for non-invasive in vivo assessment of ER activity in tumors. This study utilizes 18F-FES PET imaging as a pharmacodynamic biomarker in patients with ER+ tumors treated with Z-endoxifen. METHODS: Fifteen patients were recruited from a parent therapeutic trial of Z-endoxifen and underwent imaging with 18F-FES PET at baseline. Eight had positive lesions on the baseline scan and underwent follow-up imaging with 18F-FES 1-5 days post administration of Z-endoxifen. RESULTS: Statistically significant changes (p = 0.0078) in standard uptake value (SUV)-Max were observed between the baseline and follow-up scans as early as 1 day post drug administration. CONCLUSION: F-FES PET imaging could serve as a pharmacodynamic biomarker for patients treated with ER-directed therapy.

Long-term efficacy of a hepatitis E vaccine.

BACKGROUND: Hepatitis E virus (HEV) is a leading cause of acute hepatitis. The long-term efficacy of a hepatitis E vaccine needs to be determined. METHODS: In an initial efficacy study, we randomly assigned healthy adults 16 to 65 years of age to receive three doses of either a hepatitis E vaccine (vaccine group; 56,302 participants) or a hepatitis B vaccine (control group; 56,302 participants). The vaccines were administered at 0, 1, and 6 months, and the participants were followed for 19 months. In this extended follow-up study, the treatment assignments of all participants remained double-blinded, and follow-up assessments of efficacy, immunogenicity, and safety were continued for up to 4.5 years. RESULTS: During the 4.5-year study period, 60 cases of hepatitis E were identified; 7 cases were confirmed in the vaccine group (0.3 cases per 10,000 person-years), and 53 cases in the control group (2.1 cases per 10,000 person-years), representing a vaccine efficacy of 86.8% (95% confidence interval, 71 to 94) in the modified intention-to-treat analysis, rather than (95% confidence interval, 71 to 84) [corrected]. Of the participants who were assessed for immunogenicity and were seronegative at baseline, 87% of those who received three doses of the hepatitis E vaccine maintained antibodies against HEV for at least 4.5 years; HEV antibody titers developed in 9% in the control group. The rate of adverse events was similar in the two groups. CONCLUSIONS: Immunization with this hepatitis E vaccine induced antibodies against HEV and provided protection against hepatitis E for up to 4.5 years. (Funded by the Chinese Ministry of Science and Technology and others; ClinicalTrials.gov number, NCT01014845.).

Protection against hepatitis E virus infection by naturally acquired and vaccine-induced immunity.

Immunity acquired from infection or vaccination protects humans from symptomatic hepatitis E. However, whether the risk of hepatitis E virus (HEV) infection is reduced by the immunity remains unknown. To understand this issue, a cohort with 12 409 participants randomized to receive the hepatitis E vaccine Hecolin(®) or placebo were serologically followed up for 2 years after vaccination. About half (47%) of participants were initially seropositive. A total of 139 infection episodes, evidenced by four-fold or greater rise of anti-HEV level or positive seroconversion, occurred in participants who received three doses of treatment. Risk of infection was highest among the baseline seronegative placebo group participants (2.04%). Pre-existing immunity and vaccine-induced immunity lower the risk significantly, to 0.52% and 0.30%, respectively. In conclusion, both vaccine-induced and naturally acquired immunity can effectively protect against HEV infection.